This proposal is to establish a Center of Biomedical Research Excellence; (COBRE) on "Mechanisms of Cardiovascular Remodeling". Cardiovascular diseases account for nearly half of all deaths in the US. In recent years, it has become widely recognized that pathological remodeling of the cardiovascular system may not be simply a consequence of hemodynamic derangements but may play a primary role in the disease process. Therapeutic interventions that prevent or reverse remodeling in the head, blood vessels, and kidneys clearly lead to a reduction in mortality and improvement in quality of life. The associated neurohumoral and molecular/signaling mechanisms are poor y understood. Realizing the enormous therapeutic implications of discoveries in this field, the University of South Dakota School of Medicine has made a conscious effort to assemble a team of investigators to focus on work in cardiovascular remodeling. Four promising new faculty with research interests in this area have been recruited recently. Each have trained with world-renowned investigators. The COBRE Director is an internationally recognized expert in cardiovascular remodeling. Two other NIH funded faculty with cardiovascular expertise will provide additional mentoring and technical assistance. Cumulatively, the group has expertise in physiology, pharmacology, morphology, molecular biology, signal transduction, transgenesis, genomics, and proteomics. COBRE funding will facilitate our promising junior scientists in developing productive. NIH-funded research programs and will add depth and additional expertise to the croup. We believe the end result will be an internationally recognized research program that makes substantial contributions to the field. The COBRE contains four projects and four cores (including administration). Project 1, led by Dr. Xuejun Wang, will define the pathogenic role of the ubiquitin-proteasome system in cardiac remodeling in failure. Project 2, led by Dr. Faqian Li, will test the role of a key signaling pathway in cell growth leading to chamber dilatation in heart failure. Project 3, led by Dr. Rachid Kacimi, will examine the role of newly discovered cytokines in ischemic heart failure.